ArticleBMC medical genomics2015
Loss of heterozygosity: what is it good for?
Article in BMC medical genomics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed.
- Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study.Prostate cancer and prostatic diseases · 2025Trial
- Gallbladder cancer with dual genetic variants of PMS2 and BRCA2: a case report.Clinical journal of gastroenterology · 2026Article
- Burst of aneuploidy: a cost of adaptation driven by breakdown of cell cycle control.Molecular systems biology · 2026Article
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- Treating microsatellite unstable metastatic parathyroid carcinoma with anti-PD1 therapy.JCEM case reports · 2026Article
- Genome doubling as a dynamic driver of ovarian cancer evolution: insights from single-cell sequencing.Journal of ovarian research · 2025Review
- Loss of Heterozygosity in Pediatric Acute Lymphoblastic Leukemia and Its Prognostic Impact: A Retrospective Study.Cancers · 2025Article
- Glioblastoma at the crossroads: current understanding and future therapeutic horizons.Signal transduction and targeted therapy · 2025Review
- BRCA1 Promoter Methylation in Ovarian Cancer: Clinical Relevance and a Novel Diagnostic Approach Using Fragment Analysis.Cancer science · 2025Article
- The dynamics of loss of heterozygosity events in genomes.EMBO reports · 2025Review
- Biophysical Properties of Somatic Cancer Mutations in the S4 Transmembrane Segment of the Human Voltage-Gated Proton Channel hHBiomolecules · 2025Article
- Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing.NPJ genomic medicine · 2025Article
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- Hybrid adaptation is hampered by Haldane's sieve.Nature communications · 2024Article
- Review
- KaryoTap Enables Aneuploidy Detection in Thousands of Single Human Cells.bioRxiv : the preprint server for biology · 2024Article
- Article
- Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations.Nature communications · 2024Article
- A Synopsis of Biomarkers in Glioblastoma: Past and Present.Current issues in molecular biology · 2024Review
- Cancer predisposition signaling in Beckwith-Wiedemann Syndrome drives Wilms tumor development.British journal of cancer · 2024Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLoss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele.
methodsWe analysed 86 ovarian carcinomas for mutations in 980 genes selected on the basis of their location in common regions of LOH.
resultsWe identified 36 significantly mutated genes, but these could only partly account for the quanta of LOH in the samples. Using our own and TCGA data we then evaluated five possible models to explain the selection for non-random accumulation of LOH in ovarian cancer genomes: 1. Classic two-hit hypothesis: high frequency biallelic genetic inactivation of tumour suppressor genes. 2. Epigenetic two-hit hypothesis: biallelic inactivation through methylation and LOH. 3. Multiple alternate-gene biallelic inactivation: low frequency gene disruption. 4. Haplo-insufficiency: Single copy gene disruption. 5. Modified two-hit hypothesis: reduction to homozygosity of low penetrance germline predisposition alleles. We determined that while high-frequency biallelic gene inactivation under model 1 is rare, regions of LOH (particularly copy-number neutral LOH) are enriched for deleterious mutations and increased promoter methylation, while copy-number loss LOH regions are likely to contain under-expressed genes suggestive of haploinsufficiency. Reduction to homozygosity of cancer predisposition SNPs may also play a minor role.
conclusionIt is likely that selection for regions of LOH depends on its effect on multiple genes. Selection for copy number neutral LOH may better fit the classic two-hit model whereas selection for copy number loss may be attributed to its effect on multi-gene haploinsufficiency. LOH mapping alone is unlikely to be successful in identifying novel tumour suppressor genes; a combined approach may be more effective.
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